Identification of serological markers of protection and risk for dengue vaccines and natural infection

鉴定登革热疫苗和自然感染的保护和风险的血清学标记

• 批准号: 10638037
• 负责人: Derek A Cummings
• 金额: $ 69.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638037
• 关键词: Acute; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antigenic Specificity; Antigenic Variation; Attenuated; Automobile Driving; B-Lymphocytes; Biological; Biological Assay; Collection; Complement Activation; Country; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Dimensions; Disease; Effectiveness; Evaluation; Failure; Grant; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunological Models; Immunologics; Immunology procedure; Individual; Infection; Label; Licensing; Licensure; Life Cycle Stages; Link; Longterm Follow-up; Measures; Mediating; Memory; Memory B-Lymphocyte; Modeling; Outcome; Participant; Performance; Peripheral Blood Mononuclear Cell; Philippines; Population; Public Health; Recording of previous events; Risk; Risk Assessment; Risk Marker; Role; Safety; Sampling; Severities; Severity of illness; System; T cell response; T-Lymphocyte; Thailand; Time; United States National Institutes of Health; Vaccinated; Vaccination; Vaccinee; Vaccines; Work; antibody-dependent cell cytotoxicity; cohort; design; disorder risk; epidemiology study; experience; follow-up; immunological diversity; improved; infection risk; mathematical model; pathogen; phase 3 testing; recruit; response; serological marker; unvaccinated; vaccine candidate; vaccine development; vaccine evaluation; vaccine trial

Project Summary Dengue remains stubbornly endemic in many countries. Vaccine development efforts have been hampered by a poor understanding of the immune response. We do know that pre-existing immunity from vaccination or historic infections is key to driving disease risk, however, accurate markers of risk or protection are lacking, including how they change over multiple years. Less is known about the role of non-neutralizing antibody functions, such as antibody-dependent cell cytotoxicity, and antibody-dependent enhancement in driving disease risk. Neutralizing and non-neutralizing antibody responses have not been characterized alongside cellular immune responses that have been identified to be associated with risk of illness. Here, we will expand upon previous work on the diversity of neutralization responses to specifically add characterization of non-neutralizing antibody responses and cellular immune responses from natural infection and vaccination using samples taken from the same individuals over numerous time points. These samples come from cohorts that had regular collection of sera and PBMC and were followed for instances of infection and illness, many of which severe. This includes a cohort of individuals that were vaccinated by the only licensed dengue vaccine, a cohort followed for 13 years. We also have access to samples from individuals vaccinated with another candidate vaccine followed over five years. Finally, we will re-recruit cohort participants to provide samples 23 years after their participation to investigate long term responses after infections. We will measure multiple non-neutralizing and neutralizing responses to a diverse set of dengue viruses a wide range of antibody measures as well as a limited set of cellular immune responses, providing a multi-dimensional, systems characterization of humoral and cellular immune responses. We will use this multi-dimensional measure and mathematical models to reconstruct full infection histories and immune dynamics. These efforts will provide a set of correlates of protection/risk of illness and infection that can be used to assess risk in vaccine trials and epidemiological studies. These mechanistic models will be generally useful to infer dynamics of immune responses to antigenically variable pathogens and can be used to assist in the design and analysis of vaccine trials and epidemiological studies. Relevance to Public Health Multiple candidate dengue vaccines are currently in development, however, their likely effectiveness over short and long time periods remain unknown due to a lack of good markers of protection or risk. Identifying such markers, and how they change over time is critical to their optimal use, continued efficacy and population safety. More broadly, characterization of non-neutralizing antibody and cellular immune responses to a diverse set of dengue viruses alongside neutralizing responses in humans followed over many years who have experienced dengue infection and/or vaccination will increase our understanding of immune responses to dengue.

项目摘要 登革热在许多国家仍然是顽固的地方病。疫苗开发工作受到阻碍， 对免疫反应缺乏了解。我们知道，预先存在的免疫接种或 历史感染是推动疾病风险的关键，然而，缺乏准确的风险或保护标志， 包括它们多年来的变化。对非中和抗体的作用知之甚少 功能，如抗体依赖性细胞毒性和抗体依赖性增强驱动疾病 风险中和和非中和抗体反应尚未与细胞免疫反应一起表征。 免疫反应已被确定为与疾病的风险有关。在这里，我们将扩展到 先前关于中和反应多样性的工作专门增加了非中和反应的表征 来自自然感染和接种疫苗的抗体应答和细胞免疫应答， 同一个人在不同的时间点这些样本来自于那些定期 收集血清和PBMC，并跟踪感染和疾病的情况，其中许多是严重的。这 包括接种了唯一许可的登革热疫苗的一组个体， 13年我们还可以获得接种另一种候选疫苗的个体的样本， 超过五年。最后，我们将重新招募队列参与者，在他们参与23年后提供样本 研究感染后的长期反应。我们将测量多个非中和和中和 对各种登革热病毒的反应，广泛的抗体措施以及有限的 细胞免疫应答，提供体液和细胞免疫应答的多维系统表征， 免疫反应。我们将使用这种多维测量和数学模型来重建完整的 感染史和免疫动力学这些努力将提供一套保护/疾病风险的相关因素 和感染，可用于评估疫苗试验和流行病学研究的风险。这些机械 模型通常可用于推断对抗原可变病原体的免疫应答的动力学， 可用于协助疫苗试验和流行病学研究的设计和分析。 与公共卫生的相关性 目前正在开发多种候选登革热疫苗，然而，它们可能的有效性超过短期 并且由于缺乏良好的保护或风险标记，长时间内仍然未知。识别此类 标记物及其随时间的变化对它们的最佳使用、持续有效性和人群安全性至关重要。 更广泛地说，非中和抗体和细胞免疫反应的表征，以不同的一组， 登革热病毒以及人类的中和反应进行了多年的研究， 登革热感染和/或疫苗接种将增加我们对登革热免疫反应的理解。